ABSTRACT The central mechanisms that cause hypertension, a public health crisis that affects 1 in 3 U.S. adults, remain largely unknown. Our pilot data demonstrate that hypothalamic paraventricular (PVN) specific G?i2-subunit protein-gated pathways, which are activated in response to high salt intake by the afferent renal nerves, modulate PVN anti-inflammatory responses and PVN parvocellular neuron evoked sympathoinhibitory and natriuretic responses to salt-intake. Additionally, PVN specific G?i2 protein up regulation is required to counter salt-sensitive hypertension. Further, our pilot data suggests that GNIA2 polymorphic variance represents a novel clinical biomarker of the salt-sensitivity of blood pressure. This application will test the overall hypothesis that dietary sodium evoked afferent renal nerve-dependent up regulation of PVN G?i2-subunit protein-gated pathways augments parvocellular sympathoinhibitory responses to counter the development of salt-sensitive hypertension and that GNAI2 polymorphic variance is a clinical biomarker of the salt-sensitivity of blood pressure. The following Specific Aims will be conducted to test this hypothesis - Specific Aim 1: To establish that PVN G?i2-subunit proteins modulate PVN parvocellular sympathoinhibitory neuronal activation and inflammation to counter the initiation of salt-sensitive hypertension. Specific Aim 2: To establish that the afferent renal nerves stimulate PVN G?i2-subunit protein up regulation to potentiate PVN parvocellular- mediated sympathoinhibitory and natriuretic responses to counter the initiation of salt-sensitive hypertension. Specific Aim 3: To establish that polymorphic variance in the GNAI2 gene is a clinical biomarker for the salt- sensitivity of blood pressure. These studies are central to the mission of the National Heart Lung and Blood Institute (NHLBI) and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies directly address the 2014 NHLBI Salt in Human Health and Sickness Working Group recommendations for 1) a need to further illuminate the biological mechanisms and pathological processes to which salt may contribute, 2) salt-sensitive hypertension as a priority research topic and, 3) the development of standardized protocols to determine the salt-sensitivity of blood pressure at an individual level. Our research goals will be accomplished by a multidisciplinary collaborative research team that combines the use of salt-resistant and salt-sensitive rat models (Aims 1 & 2) and defined salt-sensitive and salt-resistant patient samples (Aim 3) to generate mechanistic insight and clinical relevance simultaneously. By investigating the PVN G?i2 mediated neural mechanisms underlying salt-sensitive hypertension and the utility of GNAI2 polymorphisms to determine the individual salt-sensitivity of blood pressure, our innovative research strategy will define a novel dietary sodium-sensitive mechanism that prevents the initiation of salt-sensitive hypertension (i.e., the afferent renal nerves), develop a clinical diagnostic biomarker (i.e., GNAI2 polymorphic variance) and identify mechanistic sympathoinhibitory therapeutic targets (e.g., G?i2 proteins) for the treatment of salt-sensitive hypertension.